The term “dysphagia,” which refers to a difficulty in swallowing, is common among all age groups. According to one study, people having dysphagia problems make up about 35% of the general population and an additional 30-40% of elderly institutionalized patients as well as 18-22% of all persons in long-term care facilities [see, e.g., Sastry, S. et al., Pharm. Sci. & Tech. Today 3: 138-145, 2000]. Common complaints related to difficulty in swallowing tablets are tablet size, surface, form and taste (in the order of frequency of complaints). Geriatric and pediatric patients, as well as traveling patients who may not have ready access to water, prefer dosage forms that can be taken without water and that can be easily swallowed. Another study has shown that an estimated 50% of the population suffers from difficulty in the swallowing of tablets [Seager, H., J. Pharm. Pharmacol. 50: 375-382, 1998]. Solid dosage forms that can be disintegrated, dissolved, or suspended by saliva in the mouth resulting in easy swallowing can provide significant benefits to the pediatric and geriatric population, as well as other patients who prefer the convenience of easily swallowable dosage forms.
During the last decade, fast dissolving tablet technologies that make tablets disintegrate in the mouth without additional water intake have drawn a great deal of attention. This novel technology of fast-dissolving tablets is also known as fast-dispersing, rapid-dissolve, rapid-melt and/or quick-disintegrating tablets. A fast-dissolving tablet usually disintegrates into smaller granules which slowly dissolve in the mouth. The disintegration time for fast dissolving tablets varies from a few seconds to more than a minute depending on the formulation and the size of the tablets. The fast dissolving tablets provide patients a convenient alternative to traditional tablets or capsules, which have to be administered with water, and to a liquid dosage form, which is typically bulkier and less accurate in dose. Fast dissolving tablets are particularly needed by the elderly, children, and many others who have difficulty in swallowing.
As used herein, the term “fast-melting tablet” refers to a novel formulation whereby a solid tablet disintegrates into smaller particles resulting in a paste-like structure that can be easily swallowed or dissolved completely in the mouth. Since the terms “fast dissolving tablets” and “fast disintegrating tablets” have been used widely in the literature, they are also used herein to refer to background aspects of the invention and other technologies. As used herein, “FDT” refers to either “fast-dissolving tablet” or “fast-disintegrating tablet.”
Processes for Making Fast-Dissolving Tablets
Several technologies have been used previously to produce commercially available FDTs. For example, ZYDIS® (Cardinal Health; Dublin, Ohio), ORASOLV® and DURASOLV® (Cima Labs, Inc.; Eden Prairie, Minn.), and WOWTAB® (Yamanouchi Pharma Technologies, Inc.; Palo Alto, Calif.) technologies have been used to make products in the U.S. market. Although these technologies meet the special requirements for FDTs to some extent, none of them has all the desired properties. For example, to maximize the porous structure of the tablets, current FDT technologies utilize appropriate disintegrating agents and/or highly water-soluble excipients in the tablet formulation. Currently available technologies have been reviewed in the literature [see, e.g., Sastry, S., supra; Seager, H., J. Pharm. Pharmacol. 50: 375-382, 1998; and Bogner, R., et al., U.S. Pharmacist 27: 34-43, 2002]. The technologies are usually grouped according to the process used in making FDTs, i.e., freeze-drying, molding or compression processes.
Freeze-drying process: Freeze-drying (lyophilization) is a process in which solvent is removed from a frozen drug solution or a frozen drug suspension containing structure-forming excipients. The resulting tablets are usually very light and have porous and plastic structures that allow rapid dissolution. When placed on the tongue the unit dissolves almost instantly to release the incorporated drug. The entire freeze drying process is done at non-elevated temperatures, therefore, eliminating adverse thermal effects that may affect the drug stability during processing. When stored in a dried state, this dosage form has relatively few stability problems during shelf-life. The ZYDIS technology is described in U.S. Pat. No. 4,371,516 (issued to Gregory et al.) and U.S. Pat. No. 5,738,875 (issued to Yarwood et al.). Freeze drying is a relatively expensive manufacturing process and the final dosage forms are very fragile, lacking physical resistance in standard blister packs. Moreover, this approach does not permit accommodating high amounts of active drugs. Additionally, the water soluble drugs may form eutectic mixtures that can not be frozen adequately to form a rigid structure necessary to support itself after solvent is removed, which may cause collapse of the freeze dried cake, and for this reason, the dose for water soluble drugs is usually limited to 60 mg [Seager, H., supra].
Molding process: The major components of molded tablets are typically water-soluble ingredients. The powder mixture is moistened with a solvent (usually water or ethanol), and then the mixture is compressed into mold plates to form a wetted mass (compression molding). The wet mass is molded into tablets under pressures lower than those used in conventional tablet compression. The solvent evaporates by air-drying. Because molded tablets are much less compact than compressed tablets, a higher porous structure is created which enhances dissolution. To improve rapid dissolution, the powder blend usually has to be pushed through a very fine screen. Recently, the molded forms have also been prepared directly from a molten matrix in which the drug is dissolved or dispersed (heat molding) or by evaporating the solvent from a drug solution or suspension at ambient pressure (no-vacuum lyophilization) [Dobetti, L., Pharmaceutical Technology North America, Suppl. (Drug Delivery), 44-50, 2001]. Because the major component in the dispersion matrix is generally made from water-soluble sugars, molded tablets disintegrate more rapidly and offer improved taste. Unfortunately, molded tablets typically do not have great mechanical strength. See, e.g., U.S. Pat. No. 5,082,667 (issued to Van Scoik). The chances of erosion and breakage of the molded tablets during tablet handling and opening blister pockets are high. By using nonconventional equipment and/or multistep processes, FDTs with both adequate mechanical strength and good disintegration have been prepared by molding techniques. Using a nonconventional approach, however, requires more investment in machinery. As compared with FDTs prepared by freeze-drying, molded tablets can be produced more simply and efficiently on an industrial scale, although disintegration times are not comparable to those of lyophilized forms.
Compression process: Using a conventional tablet press for making fast dissolving tablets is very attractive because of low manufacturing cost and ease in technology transfer. However, a tablet press has been designed to make conventional tablets. When making conventional tablets, maintaining high tablet porosity is not a primary concern. High compression force is used to ensure the tablet strength. Many strategies have been tried to achieve high porosity and adequate tablet strength using the tablet press. The compression process is most widely used for making FDTs. The three widely used approaches are: granulation methods, special excipients methods, and compaction and subsequent treatment methods. Because the present invention is related to the compression method, the aforementioned approaches are described below in detail.
Granulation methods: Wet granulation, dry granulation, spray drying, and flash heating methods are all distinct methods used to obtain granules for making FDTs. These methods are briefly discussed hereinbelow.
a. Wet Granulation
U.S. Pat. No. 6,149,938 (issued to Bonadeo et al.) proposes a process of producing rapidly disintegrable, mouth-soluble tablets by wet granulation in a fluidized bed. The inventors claim that even with effervescent agents presented in the tablet with lower than 5%, similar quick disintegration times can be achieved. Furthermore, they found that fast disintegration times can be achieved using only the acid component of the effervescent couple. They suggest use of polyalcohols (e.g., mannitol, xylitol, sorbitol, maltitol, erythritol and lactitol), 1-30% of an edible acid, and an active ingredient as the dry mixture. This mixture was wet granulated with an aqueous solution of a water-soluble or water-dispersible polymer (e.g., poly(ethylene glycols), carrageenan, and ethylcellulose) which consists 1-10% of the final weight of the granule in a fluid bed. Granules with high porosity and low apparent density were obtained, and the tablets made by such granules are reported to have rapidly disintegration time ranging from 3 to 30 sec in the saliva.
U.S. Pat. No. 6,316,029 (issued to Jain et al.) proposes a rapidly disintegrating tablet for a poorly soluble active ingredient. First, nanoparticles were formed by mechanical grinding, precipitation, or any other suitable size reduction process. Those nanoparticles, less than 2,000 nm, were attached to the surface stabilizer, such as nonionic and ionic surfactants. The particles were granulated with at least one pharmaceutically acceptable water-soluble or water-dispersible excipient using a fluid bed; the granules were made into tablets. The tablets had complete disintegration or dissolution in less than 3 min.
b. Dry Granulation
U.S. Pat. No. 5,939,091 (issued to Eoga et al.) proposes a method of making FDTs by dry granulation. Higher density alkali earth metal salts and water soluble carbohydrates do not provide quick disintegration and a smooth mouth feel. Low density alkali earth metal salts and water soluble carbohydrates are difficult to compress and may cause inadequate content uniformity. Thus, low density alkali earth metal salts or water soluble carbohydrates were pre-compacted, and the resulting granules were compressed into tablets that could dissolve fast. In this process, a powdered material with a density of 0.2-0.55 g/ml was pre-compacted to increase the density to 0.4-0.75 g/ml by applying a force speed ranging from about 1.0 kN/cm to about 9.0 kN/cm. The resulting granules were compressed into tablets.
c. Spray Drying
Spray-drying provides a fast and economical way of removing solvents and producing porous and plastic, fine powders. U.S. Pat. No. 6,207,199 (issued to Allen et al.) proposes a particulate support matrix for use in forming fast-dissolving tablets by using a spray-drying technique. The components in this particulate support matrix include supporting agents composed of two polypeptide components of the same net charge (preferably non-hydrolyzed gelatin and hydrolyzed gelatin), a bulking agent (mannitol), and a volatilizing agent. The mixtures of above components were spray dried to obtain porous granules. By incorporating a volatilizing agent (in most cases, ethanol), the surface tension of the droplets was further reduced during spray-drying and more pores and channels were created. The solubility of the matrix was further increased (in a matter of seconds) when combined with a bulking agent. A minimal amount of effervescent agents may be optionally included to further accelerate the dissolution rate. To aid in keeping the tablets intact during handling, a thin coating of polymeric material may also be applied externally. Active ingredients can be micro-encapsulated or nano-encapsulated to further achieve taste-masking.
d. Flash Heat Process
Fuisz et al. have introduced the shearform technologies to make FDTs. This technology, as described in PCT Publication WO 95/34293 and U.S. Pat. No. 6,048,541 utilizes a unique spinning mechanism to produce a floss-like crystalline structure, much like cotton candy. In this process, the feedstock is subjected to centrifugal force and to a temperature gradient simultaneously. An internal flow is created by this condition to force the flowing mass out of the opening provided in the perimeter of a spinning head. The mass is cooled down as it comes out of the opening to form a discrete fiber structure, as seen in cotton candy. The speed of spinning is about 3,000-4,000 rpm and the temperature gradient is about 180-250° C. The carrier materials include saccharides, polysaccharides, and mixtures thereof. The produced floss needs to be recrystallized to form freely flowing granules with self-binding properties.
Specific excipients methods: These methods focus on selecting specific excipients, such as water-insoluble calcium salt, specific disintegrant combination, and specific sugar combination, as the main component for FDTs.
a. Calcium Salt as the Specific Excipient
U.S. Pat. No. 6,596,311 (issued to Dobetti) proposes a formulation using insoluble inorganic excipients as the main component for fast disintegration tablets. According to this reference, disintegration of a tablet in the oral cavity depends on the quantity of the disintegrant and insoluble inorganic excipient used. The disintegration also depends on the relative weight ratio between the water insoluble and soluble excipients, if the water soluble excipients are used. It was also found that in their formulation, sufficient compression could be applied to form tablets with strong tensile strength and low friability. The disintegration rates reportedly were not significantly affected by the high compression force. Substantially water insoluble components include water-insoluble excipients, water-insoluble drugs (either coated or uncoated), and water-insoluble lubricant and glidant. The water-insoluble excipients include insoluble inorganic salt (e.g., di- or tri-basic calcium phosphate) or organic filler (e.g., microcrystalline cellulose).
b. Sugar Based Excipients
Sugar-based excipients, such as sorbitol, mannitol, dextrose, xylitol, fructose, maltose, isomalt, maltitol, lactitol, starch hydrolysate, and polydextrose, have been widely used as bulking agents because of their high aqueous solubility and sweetness, pleasing mouth-feel and good taste masking. Nearly all formulations for rapidly dissolving tablets incorporate some sugar materials in their formulations [Chang, R.-K., et al., Pharmaceutical Technology, 24: 52-58, 2000].
A further proposal is described in U.S. Pat. No. 5,576,014 (issued to Mizumoto et al.), U.S. Pat. No. 6,589,554 (issued to Mizumoto et al.) and U.S. Pat. No. 6,465,009 (issued to Liu et al.), which related to the so-called WOWTAB® technology of Yamanouchi Pharmaceutical Co. This technology employs a combination of low and high moldability saccharides to produce fast dissolving tablets using conventional granulation and tableting techniques. As set forth in these references, saccharides are divided into two groups: saccharides with high moldability and low moldability. The saccharides having “low moldability” are those producing tablets with a hardness between 0-2 kg when 150 mg of such a saccharide is compressed under pressure of 10-50 kg/cm2 using a die of 8 mm in diameter. Exemplary low moldability saccharides include lactose, mannitol, glucose, sucrose, and xylitol. The saccharides having “high moldability” are those producing tablets with hardness above 2 kg when prepared under identical conditions. Typical high moldability saccharides consist of maltose, maltitol, sorbitol and oligosaccharides. When tablets are made by compressing a saccharide having low moldability or a saccharide having high moldability alone, the desired properties of adequate hardness and quick disintegration in the mouth reportedly cannot be achieved simultaneously. Moreover, if a saccharide having low moldability and a saccharide having high moldability are mixed (physical mixture) before tableting, quick disintegration and dissolution in the mouth cannot be obtained. According to these references, no single saccharide can make tablets having both high strength and fast disintegration properties. For this reason, a saccharide having low moldability was granulated with a saccharide having high moldability as a binder. The low moldability saccharides were used as the main component. The blending ratio of a high moldability saccharide to the low moldability saccharide ranged from 2 to 20% by weight, preferably from 5 to 10% by weight. Up to 50% (w/w) of the tablet weight can be the active ingredient in these systems. Tablets made by compression of these granules are claimed to show an adequate hardness and fast disintegration and dissolution when put in the mouth.
c. Disintegrants
Most fast dissolving tablet formulations use some type of disintegrant. Some formulations use effervescent couples as their disintegrant, while others use a combination of disintegrants. A summary of different types of non-effervescent disintegrants used in the pharmaceutical area is given by Dobetti (U.S. Pat. No. 6,596,311).
As disclosed by U.S. Pat. No. 5,464,632 (issued to Cousin et al.), the FLASHTAB® technology of Laboratoires Prographarm (France) produces tablets by compression of granular excipients. Excipients used in this technology comprise two groups of components. One group is disintegrating agents, such as carboxymethylcellulose or insoluble reticulated polyvinylpyrrolidone. The other group is swelling agents, such as carboxymethylcellulose, starch, modified starch, carboxymethylated starch, microcrystalline cellulose, and possibly directly compressible sugars. The mixture of excipients was prepared by either dry or wet granulation methods. The produced tablets are known to have satisfactory physical resistance and disintegrate in the mouth within 1 min.
U.S. Pat. No. 5,178,878 (issued to Wehling et al.), proposes the ORASOLV® technology of Cima Labs, Inc. This references discloses a low pressure compression method of making fast dissolving tablets that uses an effervescent disintegration agent. Effervescent disintegration agents are compounds that release gas as they contact water. The most widely used effervescent disintegration pairs usually include an acid source and a carbonate source. The acid source includes citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acids. The carbonate source includes sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate. The carbon dioxide evolved from the reaction may provide patients some “fizzing” sensation, which is a “positive” organoleptic sensation. Formulations described in the patent include an effervescent disintegration agent, a pharmaceutical ingredient in a microparticle form, and other excipients such as binders and non-effervescent disintegrants. The amount of an effervescent disintegration agent is in general about 20-25% of the total weight of the tablet. A pharmaceutical ingredient incorporated in the tablet is in a microparticle form. The microparticles may be prepared as a microcapsule or as a matrix-type microparticle. The microparticle form can also be used to cover the bad taste of drugs as well as to control the drug release profiles. Because of the soft and fragile nature of ORASOLV® tablets, a special packaging system, referred to as PAKSOLVE and disclosed in U.S. Pat. No. 6,311,462 (issued to Amborn et al.), was developed to protect the tablets from breaking during transport and storage. Also, DURASOLV® technology was developed by the same company to provide stronger tablets for packaging in foil pouches or bottles, as described in U.S. Pat. No. 6,024,981 (issued to Khankari et al.). The key ingredients in this formulation are a non-direct compression filler and a lubricant. A very fine filler, known as a non-direct compression filler, is used as the main ingredient. The materials that can be used as non-direct compression filler are non-direct compression sugars and sugar alcohols, such as dextrose, mannitol, sorbitol, lactose and sucrose. The amount of a non-direct compression filler is usually about 60-95% of the total tablet weight.
Compaction and subsequent treatments: These methods produce tablets compressed at low pressure first and then apply various after-treatments, such as sublimation, sintering, and humidity treatments, to make soft tablets strong.
a. Sublimation
In sublimation technologies, the high porosity necessary for fast disintegration is achieved by using volatile materials. Inert solid ingredients, such as urea, ammonium carbonate, ammonium bicarbonate, hexamethylene tetramine, and camphor, can volatilize readily. When these volatile materials are compressed into tablets, they can be removed via sublimation, which generates porous structures. U.S. Pat. No. 3,855,026 (issued to Heinemann et al.) discloses a process to prepare porous tablets by sublimation. The mixtures of volatile adjuvants were made into tablets which were subsequently heated to remove the adjuvants, because a residual amount of the adjuvants in the tablet may have deleterious effects on the patients. Another method is proposed by U.S. Pat. No. 5,762,961 (issued to Roser et al.), which discloses a method to produce rapidly soluble tablets by sublimation. The components in the formulation include a volatile salt (such as ammonium bicarbonate, ammonium acetate and ammonium carbonate) in the amount of 30-50% (w/w) of the tablet, a diluent (e.g., trehalose or lactose), a binder, and other adjuvants.
b. Humidity Treatment
It is known that certain sugars change from amorphous state to crystalline state when their solution is spray-dried or used as a binder solution. Further investigations have shown that when an amorphous sugar is treated to go through the humidification and drying process, it changes to a crystalline state. This change increases the tablet strength substantially.
U.S. Pat. No. 6,589,554 (Mizumoto et al.), mentioned hereinabove, proposes humidification and drying of a drug, a sugar, and an amorphous sugar capable of transforming from amorphous to the crystalline state. The major function of the sugar is to dissolve inside the buccal cavity. The amount of the sugar in the formulation can be adjusted according to the drug content and tablet size. Preferred sugars include lactose, glucose, trehalose, mannitol, erythritol, and the like. The “amorphous sugars” are those that can form an amorphous state by spray drying, freeze-drying, or other granulation methods. The “amorphous sugars” include glucose, lactose, maltose, sorbitol, trehalose, lactitol, fructose, and the like. The crystalline form of the sugars dissolved in solvent is sprayed against the drug. The humidification and subsequent drying process is used to increase the tablet strength. The relative humidity is determined by the apparent critical relative humidity of the mixture of a drug, and an amorphous sugar. A relative humidity greater than or equal to the critical relative humidity of this mixture is chosen for the humid condition. The advantage of using amorphous sugars is that they have low critical relative humidity, so that they can absorb water even at low moisture levels. The crystalline form of the sugars has difficulty in controlling moisture absorption. Moisture absorption of the crystalline form is not sufficient enough to strengthen the tablets at a low humidity condition. If a high humidity condition is used, tablets may adhere together causing manufacturing problems. Another advantage of using amorphous sugars is that transformation of the amorphous state to the crystalline state is irreversible. The sugars in the crystalline state have a high critical moisture point. The strengthened tablets are less susceptible to moisture.
U.S. Pat. No. 6,465,009 (Liu et al.), mentioned hereinabove, discloses a system for making fast dissolving tablets by humidity treatment. Water soluble polymers are used as a binder solution. The process includes the following steps: a water soluble polymer was used as a binder solution to granulate active ingredients and other excipients, such as low modability sugars (e.g., mannitol, lactose, glucose, sucrose, and lactitol); the granules were then compressed into tablets; the tablets were humidified at relative humidity of about 50-100%; and the tablets were dried. Reportedly, the hardness of the tablet is about 0.5-12.0 kilopounds and the in vivo disintegration time is about 1 sec to 40 sec.
As disclosed in U.S. Pat. No. 6,316,026 (issued to Tatara et al.), fast dissolving tablets can be made by moisture treatment and an apparatus to handle the fragile tablets before moisture treatment. An active ingredient and one or more water-soluble saccharides were compressed at pressure between 0.01 and 0.2 ton/cm2. The tablet was then moisturized and dried to produce a porosity between 20 and 40%. The active ingredient in the formulation should be preferably less than 30%. The useful saccharides in the formulation include erythritol, xylitol and mannitol. The tablet manufacturing apparatus includes a rotary punch-press, a relay conveyor for transferring tablets, a moisturizing section, a drying section and a delivery conveyor. In the moisturizing section, the condition was set to allow tablets moisturized at 45° C., 95% relative humidity for 60 sec. In the drying section, the temperature was set to 50° C. for 60 sec. By using this apparatus the fragile tablets before moisture treatment were gently transferred throughout the process.
c. Sintering
A further method is disclosed by U.S. Pat. No. 6,465,010 (issued to Lagoviyer et al.), which describes a process that increases tablet strength by sintering the tablet components at high temperatures and resolidifying after the temperature decreases subsequently. The components in this formulation include bulk agents, structure agents, solvent, and binding agents. A bulk agent in this formulation is to provide bulk volume to the overall tablet and its content ranges from approximately 10% to 95% of the whole tablet. Suitable bulking agents include carbohydrates (e.g., sucrose, mannitol, and sorbitol), calcium carbonate, magnesium carbonate, and the like. The suitable structure agents should provide a porous support structure allowing quick dissolution of the tablets in the mouth. The structural agents include agar, gelatin, albumen, and chondroitin. The preferred structural agent was gelatin. The amount of gelatin ranged from approximately 1 to 3%. Choice of solvent to dissolve the mixture of bulking agent/structural agent is based on the ability to provide a desired porosity to the bead or granulated product upon drying. Solvents can be chosen from water, ethyl alcohol, isopropyl alcohol, or a mixture thereof. The preferred solvent is the mixture of ethyl alcohol and water in a ratio ranging from 1:1 to 1:100. The binders need to melt at the sintering stage, and form bonding among granules and resolidify as the temperature of the final sintering or heating step decreases. Binders are water soluble polymers and the preferred binding agent is poly(ethylene glycol) (PEG) with a molecular weight of approximately 1,000 to 1,000,000. PEG melts at about 50 to 90° C. PEG has the advantage of functioning both as a binder and as a capillary attractant. The amount of binding polymer ranged from 0.5% to 25% of the weight of the final product.